title: Atorvastatin counteracts aberrant soft tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6⁻/⁻).
abstract: Pseudoxanthoma elasticum (PXE), a multisystem heritable disorder with aberrant mineralization of arterial blood vessels, is caused by mutations in the ABCC6 gene. Previous studies have suggested that carriers of the ABCC6 mutations, particularly of p.R1141X, are at increased risk for coronary artery disease. In this study, we used Abcc6 (tm1Jfk) knock-out mice to determine the serum lipid profiles and examine the effects of atorvastatin on the aberrant mineralization in this model of PXE. First, serum lipid profiles at 12 weeks of age, after overnight fasting, revealed a statistically significant increase in total cholesterol and triglyceride levels in Abcc6 (tm1Jfk) mice compared to their wild-type littermates. Placing these mice at 4 weeks of age for 20 weeks on atorvastatin, either 0.01 % or 0.04 % of the diet (low statin and high statin groups, respectively), reduced the total triglyceride and cholesterol levels, which was accompanied with significantly reduced mineralization of the dermal sheath of vibrissae, a biomarker of the aberrant mineralization process in these mice. However, if the mice were placed on atorvastatin for 12 weeks at 12 weeks of age, at which time point significant mineralization had already taken place, no difference in the amount of mineralization was noted. These observations suggest that statins, particularly atorvastatin, can prevent, but not reverse, aberrant mineralization in this mouse model of PXE. For a clinical perspective, a survey of 1,747 patients with PXE was conducted regarding their present or past use of statins. The results indicated that about one third of all PXE patients are currently or have previously been on cholesterol-lowering drugs. Thus, a sizable number of patients with PXE could be subject to modulation of their mineralization processes by concomitant statin treatment.
  
  
  CONCLUSIONS
  The Abcc6 (-/-) mice serve as a model system for PXE, an ectopic mineralization disorder Abcc6 (-/-) mice were shown to have elevated serum cholesterol and triglyceride levels Feeding of the Abcc6 (-/-) mice with atorvastatin prevented connective tissue mineralization A third of patients with PXE was found to be on cholesterol-lowering therapy Atorvastatin may potentially be beneficial for patients with PXE.
authors.affiliation: Departments of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Biology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, 233 South 10th Street, Suite 450 BLSB, Philadelphia, PA, 19107, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.forename: David W
authors.initials: DW
authors.lastname: Chou
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000069059:Atorvastatin; D002114:Calcinosis; D002118:Calcium / Q000097:blood / Q000378:metabolism; D003238:Connective Tissue / Q000187:drug effects* / Q000473:pathology*; D020405:Dermis / Q000473:pathology; D004195:Disease Models, Animal; D005838:Genotype; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D011561:Pseudoxanthoma Elasticum / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018528:ATP-Binding Cassette Transporters; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011758:Pyrroles; D000069059:Atorvastatin; D002118:Calcium